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Effects of acute or chronic polychlorinated biphenyl ingestion on maternal metabolic homeostasis and on the manifestations of embryotoxicity caused by cyclophosphamide in mice

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Abstract

Diets of mice contained Aroclor 1254 (PCBs; 0, 1, 10 or 100 ppm). Some groups ingested PCBs beginning on gestation day (gd) 6 (vaginal plug positive day = gd 0) and continuing throughout pregnancy (acute exposure). Others were put on PCBs 90 days before mating and continued (chronic exposure) until all animals were sacrificed on gd 18. None of the PCBs diets had adverse effects on offspring. Chronic ingestion of 100 ppm reduced the conception rate. All chronic and acute 100 ppm pregnant mice had significantly altered ratios of liver to body weight. The aim of the different pretreatment regimens was to affect to variable degrees metabolism of cyclophosphamide (CPA). Bioactivation in the dam's liver is a prerequisite for embryotoxic effects in mice. Two doses of CPA were selected that caused malformations in 21.6% (10mg/kg) or 93.4% (16 mg/kg) of the fetuses when injected on gd 11. The interaction (enhancement, no effect, attenuation) between acute or chronic PCBs and CPA could thus be examined. Double stained fetal limbs and their bone lengths were evaluated. The observations were correlated with cytochrome P-450, the levels of which were elevated in all 100 ppm groups. The activities of enzymes coupled to this hemoprotein family were induced in maternal liver in an exposure mode and PCBs concentration-dependent manner. Body burdens of PCBs in dams and fetuses were related to diet levels in acutely, but not in chronically treated animals. Placental transfer of radioactivity from ring-labelled 14C-CPA, measured in control and 100 ppm chronic mice, was not significantly affected by PCBs. Contrary to what one would expect from the P-450 levels and presumably induced monooxygenase catalyzed CPA metabolism, the effects on limb development were attenuated. The amelioration observed in mice differs markedly from the effects recently reported in rats, where induction of CPA metabolism enhanced its teratogenicity.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Michigan State University, 48824, East Lansing, Michigan, USA

    Frank Welsch

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Dedicated to Professor Dr. med. Helmut Kewitz on the ocassion of his 65th birthday

Supported by U.S. Public Health Service grant NIH-ES02461. Presented in part at the 66th annual meeting of the Federation of American Societies for Experimental Biology in April 1982 in New Orleans, Louisiana, at the 22nd annual meeting of the Teratology Society in June 1982 in French Lick, Indiana, and at the International Symposium on PCBs in the Great Lakes in March 1982 at Michigan State University in East Lansing, Michigan.

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Welsch, F. Effects of acute or chronic polychlorinated biphenyl ingestion on maternal metabolic homeostasis and on the manifestations of embryotoxicity caused by cyclophosphamide in mice. Arch Toxicol 57, 104–113 (1985). https://doi.org/10.1007/BF00343119

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  • DOI: https://doi.org/10.1007/BF00343119

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